Aging is associated with changes in the release of neurotransmitter substances from central and peripheral nerve terminals and in the secretion of hormones from glandular tissues. These alterations may underlie the functional deficits which are often noted during the aging process and suggest an age- associated alteration in the exocytotic process. Recent studies in a number of laboratories including our own, have described the involvement of protein kinase C-mediated phosphorylation in the modulation of stimulated release of biologic substances. In preliminary studies performed in Fisher-344 rats, we have found marked age-related deterioration in the ability of protein kinase C to modulate release of brain serotonin. In the present application, we propose to explore the responsiveness to protein kinase C activation of serotonin release in brain and blood platelets as (1) a biological marker of aging, and (2) a tool for assessing physiological aging during interventions which aim to improve longevity such as dietary restriction. Specifically, we propose to (1) precisely define the age dependency of the PKC effect in two strains of rats and their Fl hybrids, which have been fed ad libitum or were food restricted, (2) test the generalizability of the effect in other neurotransmitter systems, and (3) elucidate the molecular mechanisms which underlie the loss in protein kinase C mediated response. Understanding of the fundamental role of PKC in exocytosis and how it is altered during aging will be valuable as a biologic marker of aging and a tool for assessing potential interventions of the aging process. This biologic marker, when examined in blood platelets is easily accessible for use and testing in humans.